MYH2 as a Potential Modifier of Clinical Severity in Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy(FSHD) is a genetic and heterogeneous neuromuscular disorder primarily driven by DUX4 derepression. The marked clinical variability observed among affected individuals suggests the presence of additional genetic modifiers, however underlying factors remain largely unclear. Investigating coincidental hereditary conditions within families may provide critical insights into such modifying mechanisms. We investigated a multigenerational family exhibiting the co-occurrence of FSHD and hereditary macrothrombocytopenia. Detailed neurological and hematological evaluations were performed across family members. Trio whole-exome sequencing(WES) was performed in selected individuals, followed by DNA sequencing and segregation analysis of identified genes. In silico structural analyses were performed for candidate variants. Candidate variants were additionally screened in an independent cohort with next generation sequencing. Clinical severity was assessed using the Clinical severity score(CSS), FSHD clinical score, and age-corrected CSS(ACSS). Trio-WES analysis identified a pathogenic frameshift mutation(c.1848delT) in GP1BA gene, responsible for macrothrombocytopenia. Among candidate variants located near GP1BA, a missense variant in MYH2(c.5045G > A) was prioritized due to its known association with myopathy and its involvement in DUX4-related pathways. Segregation analysis revealed that GP1BA mutations were present in five of nine FSHD-affected individuals, four of whom also harboured the MYH2 variant. Neither mutation was detected in unaffected family members. Individuals carrying the MYH2 variant consistently exhibited higher ACSS values compared to family members who did not carry the variant. Screening of MYH2 c.5045G > A (p.Arg1682His) and GP1BA c.1848delT variants in an independent cohort of 30 FSHD1 patients revealed no variant carriers, with all individuals exhibiting a wild-type genotype. Network analysis focusing on the interaction landscape between the FSHD key protein DUX4 and MYH2, using the Integrated Interactions Database(IID), revealed ACTN1 as a connecting node linking these pathways. Our findings suggest that rare MYH2 variants may act as a genetic modifier influencing the clinical severity in FSHD, which has not been previously reported. This study highlights the value of investigating co-occurring hereditary conditions to uncover novel molecular contributors to disease heterogeneity in FSHD. The potential role of MYH2 and its rare variants as genetic modifiers should be further validated in larger cohorts and functional studies.